Primary arterial hypertension (PAH) is a disease characterized by elevated pulmonary artery blood pressure, remodeling of the lung vasculature, and progressive right ventricular hypertrophy. Despite recent therapeutic advances, nearly 50% of PAH patients die within 5 years of diagnosis. The familial form of PAH is associated with heterozygous mutations in the gene encoding the type II bone morphogenetic protein receptor (BMPR2), but only a minority of individuals who carry a mutant allele develop the disease The principal investigator and his team have developed a series of genetically modified mice with BMPR2 mutations. They found that deficient BMPR2 alone does not consistently replicate PAH in mice. The investigators have found unanticipated gain-of-function effects of BMPR2 deficiency including the observation that BMPR2 heterozygous pulmonary vascular cells are more responsive to TGF[unreadable] and activin A. Moreover, the investigators have identified the first small molecule BMP inhibitor which will greatly facilitate studies of BMP signaling both in vitro and in vivo. The proposed research is divided into three aims. First, the mechanisms by which BMPR2 mutations alter responses to TGF[unreadable] and activin A, as well as their physiologic sequelae, will be elucidated using cultured pulmonary vascular cells. Second, genetically-modified mice will be used to test the hypothesis that overexpression of TGF[unreadable] and activin A leads to pulmonary vascular remodeling in BMPR2 heterozygous mice. Finally, the investigators plan to use their novel BMP inhibitor to ascertain whether BMP signaling limits pulmonary vascular remodeling in a robust rat model of PAH. The results of the proposed studies will not only provide important insights into the pathogenesis of PAH but may also provide clues as to how to prevent the development of PAH in patients with BMPR2 mutations. PUBLIC HEALTH RELEVANCE. Pulmonary arterial hypertension is a disease afflicting blood vessels in the lung and is sometimes associated with mutations in the gene encoding the type II bone morphogenetic receptor (BMPR2). However, only a minority of patients with BMPR2 mutations develop the disease. In this project, mice carrying BMPR2 mutations and a novel small molecule inhibitor of BMP signaling will be used to investigate how BMPR2 mutations contribute to the disease and potentially how to prevent individuals with BMPR2 mutations from developing PAH.